Evidence and research in rectal cancer

Radiotherapy and Oncology 87 (2008) 449–474 www.thegreenjournal.com Educational review Evidence and research in rectal cancer Vincenzo Valentinia,*, Regina Beets-Tanb, Josep M. Borrasc, Zoran Krivokapićd, Jan Willem Leere, Lars Påhlmanf, Claus Rödelg, Hans Joachim Schmollh, Nigel Scotti, Cornelius Van de Veldej, Christine Verfailliek a Department of Radiation Oncology, Università Cattolica S.Cuore, Rome, Italy, bDepartment of Radiology, University Hospital Maastricht, The Netherlands, cIDIBELL-Cancer Plan, Department of Health, Barcelona, Spain, dInstitute for Digestive Diseases, Clinical Center of Serbia, Belgrade, Serbia, eDepartment of Radiation Oncology, Radboud University Nijmegen Medical Center, The Netherlands, fDepartment of Surgery, Uppsala University Hospital, Uppsala, Sweden, gDepartment of Radiation Oncology, University of Frankfurt, Germany, hDepartment of Medical Oncology, Martin Luther University Halle-Wittenberg, Germany, iDepartment of Pathology, St. James’s University Hospital, Leeds, UK, jDepartment of Surgery, Leiden University Medical Center, The Netherlands, kESTRO Office, Brussels, Belgium Abstract The main evidences of epidemiology, diagnostic imaging, pathology, surgery, radiotherapy, chemotherapy and followup are reviewed to optimize the routine treatment of rectal cancer according to a multidisciplinary approach. This paper reports on the knowledge shared between different specialists involved in the design and management of the multidisciplinary ESTRO Teaching Course on Rectal Cancer. The scenario of ongoing research is also addressed. In this time of changing treatments, it clearly appears that a common standard for large heterogeneous patient groups have to be substituted by more individualised therapies based on clinical-pathological features and very soon on molecular and genetic markers. Only trained multidisciplinary teams can face this new challenge and tailor the treatments according to the best scientific evidence for each patient. c 2008 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 87 (2008) 449–474.  Keywords: Rectal cancer treatment; Epidemiology; Diagnostic; Endorectal ultrasound; Computerized tomography; Magnetic resonance imaging; Pathology; Surgery; Total mesorectal excision; Local excision; Combined modality therapy; Radiotherapy; Pre-operative treatment; Postoperative treatment; Radiotherapy technique; Chemotherapy; Concomitant radiochemotherapy; Adjuvant chemotherapy; Early stage; Intermediate stage; Advanced stage; Local recurrence; Acute and late toxicity; Quality of life; Follow-up; Scenario of ongoing research; Educational; Randomized clinical trial; Intraoperative radiotherapy The first decade of the 21st century is seeing a revolution in the management of rectal cancer. Although surgery is still the most important tool, the treatment has changed and is more dependent upon contributions from other colleagues. Best clinical management is increasingly delivered by a highly skilled multidisciplinary team [1]. Even if the purist claims that we do not have scientific evidence for improved patient outcome from the team discussion, the sharing of scientific knowledge, clinical procedures and educational exchange can be optimized only within regular multidisciplinary meetings. The aim of this paper is to help not only radiotherapists but also surgeons, pathologists, radiologists and medical oncologists to contribute to the multidisciplinary team, exploiting knowledge shared between different specialists involved in the design and management of the multidisciplinary ESTRO Teaching Course on Rectal Cancer. In this review, we will focus on the main features of epidemiology, diagnostic imaging, pathology, surgery, radio- therapy, chemotherapy and follow-up which are used to optimize the routine treatment of rectal cancer according to a multidisciplinary approach. Epidemiology Colorectal cancer (CRC) is the third most frequent cancer in both sexes combined in Europe, after prostate and breast cancer. It has been estimated that 163,100 males and 134,100 females were diagnosed with CRC during 2006 in the 25 countries of the European Union [2], representing 13% of all cancer cases. Around 30% of all CRCs are diagnosed in the rectal anatomic site, rectal cancer affecting 49,000 males and 40,000 females in 2006 alone. A decreasing trend in the age adjusted incidence has been observed in the last decade in US [3], and in European countries incidence is stable or decreasing in most cancer registries. The highest incidence rates are found in cancer registries of the Czech Republic and Hungary and the lowest in Finland 0167-8140/$ - see front matter c 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2008.05.022  450 Evidence and research in rectal cancer (Fig. 1). However, the variability of cancer incidence, although lower than in colon cancer, suggests a strong role of environmental factors in the aetiology of this cancer. Also, a higher incidence among males is observed (Fig. 1). Mortality trends have been converging in CRC in most European countries from 1990s onwards [4]. Converging mortality rates over recent years have been reached by countries where mortality was decreasing over the last decade and in those countries (mainly Eastern and Mediterranean countries) which have experienced a recent levelling-off of mortality rates. Males Czed Republic 27. Germany 17. Norway Survival from CRC has been estimated for most European countries based on population cancer registries data in the EUROCARE project, covering incident cases from 1995 to 1999 and followed up until December 2003. CRC relative survival was 53.5% in both sexes, increasing from 49.3% in the 1990–94 period [5]. An important variability between countries was observed, however, the lowest relative survival being observed in Poland (38.8%) or in the Czech Republic (43.2%), whereas the highest was observed in Switzerland (59.7%), Norway and Sweden (58.3%) with intermediate values in Spain (52.5%) and the UK (50.6–51.8%). Differences in survival were explained to a large extent by differences in stage at diagnosis [6]. Cancer of the rectum has a similar prognosis to cancer of the colon, although in those countries where surgery has centralised (Sweden, Norway) rectal cancer now has a better prognosis [7,8]. 16. France 15. Risk factors and prevention UK 15. One question of interest regarding the aetiology of rectal cancer is the specificity of its risk factors as compared with colon cancer. The key risk factors identified for colorectal cancer as a global entity are dietary components (meat, fish, fibre, fat, folate, calcium and selenium), physical exercise, obesity and alcohol, as well as some medical therapies like Non-Steroidal Anti-inflammatory drugs (NSAIDs), Hormone Replacement Therapy (HRT), statins and oral contraceptives and medical conditions (inflammatory bowel diseases or diabetes). However, the relevant question is the potential differences in the association of those risk factors specifically with rectal as compared to colon cancer. A brief review of the most relevant risk factors is presented with emphasis on differences between colon and rectal cancer [9]. Red and processed meat intake has been associated with increased colorectal cancer risk (Risk ratio, RR = 1.55; 95% CI 1.09:2.02) in the EPIC study. This large international cohort has sufficient cases to assess the specific risk for rectal cancer cases as a separate entity. Red and processed meat significantly increases the risk of rectal cancer (RR = 1.65 95% CI 1.05:2.62) after adjustment for several relevant factors, indicating the specificity of the association although the causal mechanisms are not clear [10]. In the same study, the protective role of fish was also observed, with a RR of 0.46 (95% CI 0.27–0.77) for colorectal cancer while the RR for rectal cancer was 0.41 (95% CI 0.17:0.97). Poultry was not associated with colorectal cancer. Additionally, since fat intake is strongly related to meat intake, its independent effect on colorectal cancer risk can be disregarded. Fibre intake has been associated with colorectal cancer in some studies but not in all of them [11]. In the EPIC study, a protective association was observed, a reduction of about 9% of risk for colorectal but not for rectal cancer, after multiple adjustments for other factors, including folate intake [12]. The specificity of fibre intake from specific foods was not established. Other dietary factors such as calcium and milk intake may be associated: a higher consumption (>250 gr/day of milk) is protective for rectal cancer; (RR = 0.80; 95% CI 0.66:0.96) as well as for colon cancer [13]. Also, vitamins B, D and selenium, may play a role in the risk of colorectal cancer, although their specific role is not yet clearly established. Finally, alcohol intake (of more Spain 13. Switzerland 13. Italy 13. Poland 12. Sweden 12. 11. Finland Japan 16. 12. USA White USA Black 11. 9. China 0 5 10 15 20 25 30 20 25 30 ASR(W) Females Czed Republic Norway 12. 10. Germany 9. UK 7. France 7. Sweden 7. Italy 7. Poland 7. Switzerland 7. Spain 6. Finland 6. Japan 8. USA Black 8. USA White 7. 6. China 0 5 10 15 ASR(W) Fig. 1. Rectal Cancer Incidence in different population-based cancer registries SOURCE: Cancer Incidence in Five Continents, vol. IX. Lyon: IARC Scientific Publications, 2007 ASR(W): Age Standardized Rates World Standard Population. V. Valentini et al. / Radiotherapy and Oncology 87 (2008) 449–474 than 30 gr/day) is associated with an increased risk of rectal cancer (OR: 1.42; 95% CI 1.07:1.88) as shown in a pooled analysis of 8 cohort studies [14], as well as in the EPIC study [15]. A similar increase in risk for the rest of colon sub-sites was observed. When specific alcoholic beverages were analysed, beer and wine were associated but liquor consumption was not. Interestingly, the relative risk observed for rectal cancer was higher than that of colon cancer .subsites. Body size and body mass index (BMI) have been also investigated in the EPIC cohort study. None of these anthropometric measures were associated with increased risk of rectal cancer, although a positive association was observed for colon cancer [16]. Physical exercise has been consistently associated with colon cancer, whereas its association with rectal cancer is much weaker or negligible [17]. Several studies have suggested the protective role of aspirin and NSAIDs for both adenomas and cancer of the colorectum, although some studies have not found a significant association with rectal cancer [18]. However, adverse effects of these drugs and the unclear mechanism of any protective effect currently preclude any recommendation that they should be used for chemoprevention [19]. The relationship of statins and colorectal cancer risk has been a matter of discussion in recent years regarding their potential protective role; however, a systematic review and meta-analysis did not find a significant association [20]. Finally, ever use of oral contraceptives was shown to exert a protective effect in rectal (OR: 0.74; 95% CI 0.65:0.83) as well as in colon cancer in a meta-analysis of cohort and case-control studies [21]. Besides the modifiable risk factors mentioned above, there is a proportion of colorectal cancer (around 5–10%) that are inherited in an autosomal dominant manner [22]. The most frequent of these are familial adenomatous polyposis (FAP) and Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome, the latter being more frequent in the proximal colon [9]. It is accepted that a majority of colorectal cancer cases (around 75%) are sporadic. The rest are diagnosed in a population with first degree family relatives also affected by colorectal cancer, who have a twofold greater risk of developing bowel cancer compared to the general population [19]. Screening for colorectal cancer has been shown to be effective in reducing the mortality risk among the screened population. In a meta-analysis of randomised trials using faecal occult blood testing, a reduction of 16% in mortality was observed (95% CI 7:23%) [23]. Other screening tests, like colonoscopy or sigmoidoscopy, have been proposed and trials are being underway to test their efficacy [24]. Publication of these results in due course will help to define the best strategy for screening in this cancer. Key points: Epidemiology • Colorectal cancer (CRC) is the third most frequent cancer in both sexes combined in Europe, after prostate and breast cancer. Around 30% of all CRC cases are diagnosed in the rectal anatomic site. • In European countries incidence is stable or decreasing. CRC relative survival was 53.5% in both sexes. The lowest relative survival being observed in Poland and in the 451 Czech Republic, whereas the highest was observed in Switzerland, Norway and Sweden. • The key risk factors identified for colorectal cancer as an entity are dietary components, physical exercise, obesity and alcohol, as well as some medical therapies. • A proportion of colorectal cancer (around 5–10%) are inherited in autosomal dominant predisposition: familial adenomatous polyposis (FAP) and Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome. Individuals with a first degree relative with colorectal cancer have approximately a twofold risk of developing colorectal cancer. • Faecal occult blood test screening for colorectal cancer has been shown to be effective in reducing mortality in a screened population. Diagnostic imaging With the worldwide adoption of preoperative radiotherapy in rectal cancer surgery preoperative staging has to reach very high levels of standard and reliability. It is important to distinguish patients who only need surgery, for whom the extra costs and risks of acute and late adverse effects from radio(chemo)therapy can be avoided, from those who will have an unacceptably high risk for local failure unless preoperative therapy is given. The two foremost important factors that influence local recurrence rates after resection of rectal cancer, apart from the height of the tumour, are local tumour extent and the nodal status [25]. We will discuss the accuracy of modern imaging techniques in the preoperative prediction of T stage, CRM (circumferential resection margin) status and N stage. The tumor stage Endorectal ultrasound (EUS) is very accurate for assessing the depth of tumour growth in the bowel wall with reported overall accuracies for T staging varying between 69% and 97%. EUS remains the most accurate imaging modality for the assessment of tumor ingrowth into the rectal wall [26–31]. Two meta-analyses have shown that sensitivity was affected by the T stage [31,32]. EUS is very accurate for selection of superficial (T1 vs T2) rectal tumors from more advanced ones with reported sensitivity of 94% and specificity of 86%, but performs less well in staging the more advanced rectal cancer, T3 or T4 tumors. A report of a large endosonography study in 1184 patients with rectal tumors confirmed these findings [27]. The overall staging accuracy of 69% for EUS in this study is lower than previously reported, because the limited depth of acoustic penetration prevents accurate assessment of local tumor extent in bulky T3 and advanced rectal cancer. Another reason for the poorer results of this study is the operator dependency of EUS with significantly worse performance for non-experienced sonographers as compared to experienced ones, also reported in a prospective multicenter EUS study [33]. Although EUS is very accurate for staging superficial rectal cancer it is less suitable for the evaluation of the mesorectal excision plane, the plane that has become increasingly 452 Evidence and research in rectal cancer important to anticipate tumors at high risk of local recurrence. Planar imaging techniques such as CT and MRI do not share these disadvantages, especially MRI with a phased array coil, which has emerged as a highly accurate tool to provide anatomical information in the entire pelvic region. The advantage of an intrinsic high soft tissue contrast resolution combined with new technical developments (faster acquisitions, dedicated external coils, contrast agents, etc.) has made MRI the most promising technique for local staging of rectal cancer. Endorectal MRI can be as accurate as EUS for staging superficial tumors as shown by comparative studies between the two endoluminal techniques [28,34–36]. Endorectal MR accuracies for T staging range between 71% and 91%. However, like EUS, the mesorectal fascia and surrounding pelvic structures are difficult to visualize due to the limited field of view. Besides the technique is not widely accepted probably due to its invasive character. The newer generation phased array MRI showed T staging accuracy that was not as high as anticipated with figures varying between 65% and 86% [37–39]. One exception to these findings are those reported by Brown and colleagues who reported a 100% accuracy and complete agreement between two readers for the prediction of tumor stage with phased array MRI [40]. Most staging failures with phased array MRI occur in the differentiation between T1 vs T2 lesions and between T2 vs borderline T3 lesions with overstaging as the main cause of errors. T1 lesions, limited to the submucosa, cannot be distinguished from T2 lesions, because the submucosal layer cannot be separately visualized on phased array MRI. T2 lesions are often overstaged as T3 when there is desmoplastic reaction in front of the tumor. It is difficult to distinguish on MRI between desmoplasia without tumour cells (stage pT2) and desmoplasia with tumour cells (stage pT3) [37,40]. The circumferential resection margin (CRM) Many single center studies have shown that MRI is highly accurate for the prediction of the CRM [37,40–44] (Fig. 2a and b). The results of a systematic review of all published data so far clearly confirms the high performance of MRI for the prediction of the CRM in rectal cancer surgery [45]. The pooled data of 7 studies show a sensitivity for CRM prediction varying between 60% and 88% and specificity between 73% and 100%. From the individual studies, however, it is still unclear how often information from MRI influenced treatment, and how this was dealt with in the analysis. An audit of data on outcome of rectal resections in our department has shown that with standard use of MR in the preoperative work up the proportion of incomplete resections has been reduced by half, through better selection for neoadjuvant treatment and extensive surgery [46]. The excellent MR results of single center series are applicable in routine clinical practice as shown by the multicenter MR rectum European study (Mercury trial). MRI agreed in 82% of cases with histology for the prediction of tumour extent in the mesorectal fat. These results suggest that after a short learning curve MRI is reliable not only in expert but also in general hands [47]. Modern multislice CT is more available and faster in acquisition than MRI, and when accurate, would allow local and distant staging of rectal cancer patients in one single examination. The SPICTRE (Spiral CT in Rectal Cancer) study is a Dutch multicenter study that has investigated the CRM with the first generation 4–16 slice CT techniques in 250 patients [48]. The results suggest that first generation MSCT can be used to select high tumors with a wide CRM that are at lower risk for local recurrence. However, for low rectal cancers 4–16 slice CT was not good at all with many over and understaging errors for prediction of a free or involved resection margin. This was particularly so for less experienced readers. The inherent low contrast resolution of CT, combined with the complex tapered anatomy of the mesorectum with only little or no fatty envelope around the bowel wall, may all contribute to the low performance of CT for the evaluation of the extent of distal rectal cancer. Meanwhile advanced CT techniques with 64–128 slices are being introduced in clinical practice allowing optimal bolus timing and multiplanar reconstructions. So far, however, no data exist on its accuracy for predicting local rectal tumor Fig. 2. Sagittal and axial T2 weighted MR image of a patient with T3 low rectal cancer, approaching the pelvic floor (a, white arrows) and with involvement of the mesorectal fascia (b, white arrows). V. Valentini et al. / Radiotherapy and Oncology 87 (2008) 449–474 extent. If future studies prove its efficacy in the high risk group of low rectal cancer, then the one stop shop CT technique could become a serious competitor for MRI. The nodal stage When the treatment strategy is postoperative chemoradiotherapy for T3/N1 patients, there is little need to identify lymph node status preoperatively. When the emphasis is on preoperative (chemo)radiotherapy and one wants to select high risk patients, identifying lymph node metastases becomes essential. Identifying nodal disease is still a diagnostic problem for the radiologist. Despite the identification of lymph nodes as small as 2–3 mm on modern planar imaging, reliable detection of nodal metastases is presently not possible. CT has never been powerful for the detection of nodal disease. Only relying on size and shape criteria, CT cannot accurately distinguish between malignant and benign lymph nodes. The specific problem in rectal cancer lymph node metastasis is that many small (<5 mm) nodes may contain metastases [49]. The cut off size generally used by radiologists of >8 mm for predicting malignant nodes on CT implies that small nodes in rectal cancer are often understaged. In a recent meta-analysis of 7 studies it was shown that none of the available imaging tools were accurate enough for identification of rectal cancer nodes. EUS was the best of all, because it uses criteria such as border and echotexture in addition to size. However, EUS was only slightly superior to non-contrast enhanced MR and CT [45]. EUS guided fine needle aspiration has been reported to be a very reliable method with accuracies up to 100%, but it is a cumbersome technique that will not gain widespread acceptance. Recent developments have shown that MRI with lymph node specific contrast enhancement may be the most promising modality for distinguishing between the lower risk N0 and higher risk N1 and N2 rectal cancer patients. New MR contrast agents, like Ultrasmall Super Paramagnetic Iron Oxide (USPIO) may in the near future help radiologists to solve this difficult problem of node identification [50]. At present a Dutch multicenter study in Maastricht is evaluating the accuracy of USPIO enhanced MRI for the detection of nodal disease in rectal cancer. The results show that USPIO MRI is highly predictive for selecting N0 patients by combining morphological with functional information [51]. New Gadolinium based lymph node specific contrast agents have been reported to be promising, though all are still in preclinical stage and none of these has entered the clinical arena. Recent techniques in diagnostic oncology like FDG-PET have so far shown disappointing results for N-staging in rectal cancer. Heriot et al. demonstrated a sensitivity of only 29% for predicting lymph node involvement, probably related to the limitation of the presently available low resolution PET machines in detecting low-bulk disease [52]. Imaging after chemoradiation therapy For the identification of responders after neoadjuvant chemoradiation therapy FDG-PET has a larger role. Many studies have reported a significant decrease of standardized uptake value (SUV) on postradiation PET in responders when compared to non-responders [53–56]. 453 These favourable results were not reproduced when MRI was used for restaging. The very few studies on restaging with MRI reported many downstaging errors [54,57]. In particular downstaging to superficial tumors ypT0, ypT1,ypT2 was often misinterpreted with overstaging errors being the main error. Despite recent advances in clinical MR equipment and MR image resolution the detection of small clusters of residual tumor cells remains a problem so that at present complete remission after neoadjuvant chemoradiation can still not be reliably predicted with non-invasive imaging tools, which mainly yield morphological information about response. As MR technique advances, quantification of acquired MR data enables us to combine the morphological information on the tumor with functional information. The ability of perfusion MR techniques to monitor treatment response has been reported [58] and it will be a challenging task for future MR machines to reach such a high level of detection that they can compete with the highly sensitive PET technique. Key points: Diagnostic Imaging • There is an increasing role for imaging in the preoperative loco-regional staging of rectal cancer. The challenging task at present for preoperative imaging in rectal cancer is the identification of subgroups of patients with different risk for local recurrences, so that these patients can be stratified into a differentiated treatment strategy. • The tumor stage: Endorectal ultrasound is very accurate for selection of superficial (T1 vs T2) rectal tumors from the more advanced one, but performs less well in staging advanced rectal cancer, T3 or T4 tumors. Phased array MRI has difficulty in the differentiation between T1 vs T2 lesions and between T2 vs borderline T3 lesions with overstaging as the main cause of errors, but is highly accurate in staging advanced rectal cancer. • The circumferential resection margin (CRM): MRI is highly accurate for the prediction of the CRM. Modern multislice CT is more available and faster in acquisition than MRI, however, for low rectal cancer 4–16 slice CT is not sufficiently accurate incurring many over and understaging errors for prediction of a free or involved resection margin. • The nodal stage: Identifying nodal disease is still a diagnostic problem for the radiologist. CT cannot accurately distinguish between malignant and benign lymph nodes. EUS was only slightly superior to noncontrast enhanced MR and CT. MRI with lymph node specific contrast enhancement may be the most promising modality. FDG-PET have so far shown disappointing results for N-staging in rectal cancer. • Imaging after chemoradiation therapy: For the selection of (non-)responders after neoadjuvant chemoradiation therapy FDG-PET has a wider role. Restaging with MRI results in many errors, especially downstaging to superficial tumors ypT0, ypT1 and ypT2 was very inaccurate when the tumour has become fibrotic. The detection of small clusters of residual tumour cells among fibrosis remains a problem. 454 Evidence and research in rectal cancer Pathology Working within the multidisciplinary team the pathologist can help save lives and improve clinical management. Pathologists contribute to the prognosis given to the patient, the audit and learning processes of surgeons and radiologists, and the preoperative and postoperative treatment plan of the oncologists. They are also critical to driving our understanding of the biology of the disease and possibly the prediction of the types of therapy that the patient might respond to [59]. In this article, we will concentrate on how improving routine pathology, the dissection of the specimen, the evaluation of surgical margins, the assessment of the quality of surgery and the assessment of the rectal cancer post radiochemotherapy can contribute to better clinical outcomes. Improving routine pathology A number of audits have demonstrated the poor quality of routine pathology in day to day practice [60–62]. The Welsh CROPS study [61] showed that only 78% of colonic cancer reports and 46.6% of rectal cancer reports included all the data required to manage the patient. Extramural vascular invasion and peritoneal involvement are frequently under-reported yet directly contribute to the adjuvant treatment of colorectal cancer. Guidelines are important and there should be national or preferably international guidelines for the dissection and reporting of colorectal cancer. These need to be ‘minimum’ in that they only require essential information for the management of patients. In recognition of the importance of standards in this area the Royal College of Pathologists in the United Kingdom has created minimum datasets that have undergone widespread consultation with colleagues and professional bodies. In 1998, dissection guidelines and a colorectal minimum dataset for colorectal cancer were produced and this has gained widespread acceptance as the minimum standard for reporting this disease. It is available on the web at http://www.rcpath.org/resources/pdf/ colorectalcancer.pdf [63]. In an audit of CRC reporting in Yorkshire, England Maughan et al. have been able to demonstrate a year-on-year improvement in the quality of reporting in over 5500 colorectal cancer patients [64]. Dissection of the specimen Improving the dissection of rectal cancer is important. It is essential that senior pathologists are involved in the dayto-day activity in the cut up room, teaching trainees and raising standards amongst their colleagues. The macroscopic examination of the specimen is critical. From this an understanding of the anatomy and its variability can be obtained. An appreciation of macroscopic features helps guide pathological analysis, for example the mesorectum is thinnest near the ano-rectal junction and anteriorly between 9 and 3 o’clock. The risk of CRM involvement by tumour is therefore greatest in these areas and warrants careful examination. On receipt the anterior and posterior surfaces should be photographed to record any perforation and the plane of surgical dissection. The specimen is opened anteriorly except for the area of the tumour which is left intact to allow assessment of CRM involvement without distortion introduced by opening the bowel. The surgically created margin surfaces are painted with ink. The surgically created surface of the mesorectum is larger posteriorly and extends up to a higher level than it does anteriorly. The specimen should be fixed in formalin for 72 h or longer. It should then be described and the tumour thinly sliced (3–5 mm) transversely to a minimum of 2 cm below to 2 cm above the tumour. Good fixation allows thinner slices to be taken and thus a better assessment of tumour spread. There is usually no hurry to make a decision about further therapy and adequate time to examine the specimen should be repaid by a better, more detailed report. The slices should also be photographed in order to demonstrate the quality of surgery and for comparison with the transverse MRI images. To facilitate radiological learning a teaching set of MRI images and high-resolution digital images are presented over the web at http://www.virtualpathology.leeds.ac.uk [65]. The distance of direct tumour spread outside the muscularis propria should be recorded and the area in which tumour spreads closest to the CRM should be identified macroscopically. Blocks should be taken from the area closest to the circumferential margin and any area where the tumour extends to within less than 3 mm from the margin. Other blocks should be taken to include at least five blocks of tumour to confirm presence or absence of extramural venous invasion. Accurate nodal staging is of critical importance for selecting patients for adjuvant chemotherapy. While some centres routinely use fat clearance techniques, in most cases careful slicing of the mesorectal fat, visual inspection and palpation allows sufficient numbers of lymph nodes to be found. TNM and NICE guidance advise that at least 12 nodes should be harvested [66]. This follows studies which show a correlation between lymph node yield and N stage and a higher rate of tumour recurrence in Dukes stage B patients where small numbers of nodes are found [67,68]. Evaluation of the surgical margins Surgeons create margins that can be involved by tumour spread at a variety of sites. The most well known are the proximal and distal margins of a resection. However, surgeons are taught to avoid involvement of these margins and only 1–2% of cases in randomised trials show involvement. A further margin is the mesenteric margin where the surgeon devascularises the bowel. This is infrequently examined but we know that tumour is close to it in 8% of cases as involvement of the highest lymph node (stage Dukes C2) is recorded when reporting according to Dukes. By far the most important margin is that created around the mesorectum. This margin is under threat by direct involvement but also by the incomplete removal of lymph nodes that lie just under the mesorectal fascia, and any small deviation from the correct surgical plane could enter them, potentially compromising cure. In 1986, the Leeds group was able to demonstrate the relationship of tumour involvement of this margin with local recurrence and survival [69]. Subsequent studies by Quirke and others [70– 74] have shown that local recurrence is greatly increased and survival halved when tumour can be demonstrated with- V. Valentini et al. / Radiotherapy and Oncology 87 (2008) 449–474 455 in 1 mm of the surgical plane of resection. Only the Dutch study suggests the limit should be 2 mm [74] but this is a small group of 54 patients and is not confirmed in other studies [70–75]. The evidence base for the importance of the surgical CRM is now established. Over 4000 patients have been reported in a range of studies from audits [71,73], prospective interventions [73], and a randomised clinical trial [74,76]. All report higher local recurrence rates and lower survival when clearance is less than 1 mm. Quality of surgery The recording of the frequency of involvement of the surgical CRM is important for feedback to radiologists for accuracy of prediction as well as to the surgeon and patient as an indicator of the quality of surgery. The Leeds group have produced evidence that reducing the frequency of CRM involvement by improving surgical technique improves survival for a single surgeon [77]. Quirke first introduced the concept of pathological audit of the quality of surgery in the MRC CLASSIC [78] and CR07 [79] studies. These have recruited slowly but the concept was adopted in the Dutch TME trial [767] and there is early evidence of its value [80]. In this study despite extensive surgical training only 57% of cases were judged to be good/complete excisions with nearly one quarter of all cases (24%) assessed as a poor/incomplete excision. In the United Kingdom, each Hospital has a lead pathologist who is responsible for the performance of their colleagues in their day-to-day practice in colorectal cancer and regular audits must be undertaken to provide evidence of the quality of their practice. This may sound intimidating but poor practice wastes an opportunity to reduce morbidity and mortality from this condition. If we do not monitor our own performance then others will do so. In each case, an assessment of the quality of surgery of the mesorectum should be made by the reporting pathologist. In future, there is also likely to be greater assessment of abdomino-perineal excision specimens to gauge the amount of tissue removed at the ano-rectal junction and determine whether levator muscle is included in the resection [77]. Individual surgeons vary in how much tissue is removed from around the ano-rectal junction. In Fig. 3a, there is wide excision of the levator muscle producing a ‘‘cylindrical’’ specimen. This contrasts with the narrow waist seen at the lower end of the rectum in Fig. 3b where the surgeon has dissected from above down on to muscularis propria/internal anal sphincter and potentially exposed tumour. Preoperative chemoradiotherapy There is now good evidence that preoperative chemoradiotherapy is able to downstage rectal tumours. In around 8–30% of cases, this can lead to complete destruction of tumour cells. Early data suggests that local control can be greatly improved and this may translate into improved long-term survival in this group of patients [81]. There are a number of suggested methods for assessing such regression [82,83] which are modifications of the scoring system developed by Mandard et al. [83] for oesophageal carcinoma. The Dworak system was assessed in a preoperative 5-FU plus radiotherapy study by Rodel et al. [82,84] with Fig. 3. APR specimens: in (a) there is a wide excision of the levator muscle producing a ‘‘cylindrical’’ specimen. This contrasts with the narrow waist seen at the lower end of the rectum in (b) where the surgeon has dissected from above down on to muscularis propria/ internal anal sphincter and potentially exposed tumour. complete loss of tumour cells and the presence of very few tumour cells (defined as difficult to find microscopically), leading to a 72% relapse free survival vs 28% in tumours showing less regression. Thus, using similar grading systems the presence of very few or no tumour cells was associated with a much better outcome after therapy. It may be possible to simplify this into tumours that show an excellent response, i.e. no residual tumour cells or tumour cells that are difficult to find microscopically (Dworak 4 and 5 or Mandard 1 and 2) vs those with a poor response with easily identifiable tumour cells or no response at all (Dworak 0, 1 and 2 or Mandard 3, 4 and 5). The importance of this approach has been recently confirmed in an excellent study of preoperative radiochemotherapy vs postoperative radiochemotherapy [85]. Complete response is increasingly being used as an endpoint in studies of radiotherapy and radiochemotherapy. At a meeting of European pathologists Quirke recently proposed a pathological protocol to classify a tumour as having undergone a complete response [86]. It was agreed that where tumour cells cannot be found anywhere in the specimen on the first assessment then the whole area of the tumour will be embedded. Should no further tumour cells be 456 Evidence and research in rectal cancer seen then three levels will be taken and examined from each tumour block. If after these assessments no tumour cells are identified then the tumour should be considered to have undergone a complete response. Further levels should not be taken as it is important to standardise the degree of effort made to find the presence of tumour. Variation in sampling protocols may explain some of the big differences in the frequency of complete pathological response described in the literature. Key points: Pathology • Guidelines and computerised forms significantly improve the quality of histopathology reporting. A proposal with a widespread acceptance is available on the web at http://www.rcpath.org/resources/ pdf/colorectalcancer.pdf. • Careful macroscopic and microscopic examination of the rectal cancer specimen is vital to auditing the quality of preoperative imaging, auditing surgical technique, assessing prognosis and selecting the best adjuvant therapy. Following preoperative radiotherapy this presents particular challenges to the pathologist but a standardized approach to these specimens will allow proper comparisons to be made between different neoadjuvant protocols and assessment of new prognostic factors such as regression grade. Surgery Loco-regional tumor control in rectal cancer surgery has changed dramatically during the past 10–15 years and started with discussion of the value of more exact surgery and precise procedures following embryonic planes. This surgical technique is today called a Total Mesorectal Excision (TME) [87]. Using this technique, locally radical surgery can be achieved without compromising sphincter function. This rationale is derived from the knowledge that a rectal cancer rarely grows more than a few millimetres distally from the macroscopic margin, indicating that a distal margin of 1 cm will probably be sufficient for local cure in terms of intramural spread [88]. However, lymph node deposits in the mesorectum can be found up to 4 cm distally from the tumor [89,90]. In view of this where tumors are located in the upper third of the rectum, the mesorectum must be divided at least 5 cm from the macroscopic tumor edge if a division of the mesorectum is planned. For patients with a tumor in the middle or distal third of the rectum, a TME is always indicated if the 5 cm rule is to be followed. In the lower third of the rectum a distal macroscopic margin of 1 cm is enough after TME, as long as the dissection follows the embryonic planes and the cancer is not growing outside the fascial envelope of the mesorectum. In these situations the sphincter function can be preserved with an anastomosis created to the top of the anal canal or with an intersphincteric resection with a hand-sewn anastomosis. The efficacy of TME is closely related to the training and the case volume of each surgeon, who still represents one of the major prognostic factors in the treatment of rectal cancer [91]. In this article, we will focus on sphincter saving as a reliable end-point after preoperative radio(chemo)therapy, the surgical plane for Abdomino-Perineal Resection and the quality of life after surgery. Is sphincter saving a reliable end-point? It has been claimed, mainly based upon historical controls and not from randomized trial, that radiotherapy, and preferably chemoradiotherapy with delayed surgery will increase the number of preserved sphincters due to a downsizing effect on the tumor by induction treatment. Sphincter preservation is usually questioned where tumor is found in the lower third of the rectum. Since the mesorectum decreases in size close to the top of the anal canal, tumors arising in this area can easily invade surrounding structures, like the internal and external sphincters. If the depth of invasion exceeds a T2-tumor this is a frequent occurrence. Consequently, it is crucial to ensure that the pelvic floor is free from tumour if a loco-regional curative procedure, with the sphincters intact, is to be performed in very low rectal cancer. Sphincter preservation for rectal cancer started in the late 1940s and early 1950s, when it was obvious that rectal excision could be performed with a primary anastomosis. Before that, the surgical philosophy was that rectal cancer could spread distally outside the pelvic floor [92]. This hypothesis of tumor spread proved to be wrong however, and anterior resection has become more and more popular. As the anastomosis deep in the pelvis is rather tricky, a substantial change in the number of sphincters preserved only became obvious when stapling techniques were available in the mid 1970s [93]. Since then it is obvious from institutional series, different randomized trials and national registers that the number of patients with preserved sphincters has increased from 25% up to 50–75% [8,94]. Moreover, there are centres of excellence, where the number of patients with preserved sphincters is as high as 90%, although it is always difficult to interpret these data due to selection bias and case mix [93]. Based upon prospective populationbased registration from several national cancer registers, the proportion of patients in the total population having a sphincter-preserving procedure is around 65% [94,95]. The question is whether modern radiotherapy in a neoadjuvant setting has further changed surgical philosophy, since many surgeons presently claim that more sphincters can be preserved, provided that preoperative chemoradiotherapy is used. Unfortunately, there are no randomized trials supporting this idea [96]. When comparing new data with historical controls, one has to take into account the main changes in rectal cancer surgery during the past 10–15 years. As mentioned above a 1 cm margin is now considered good surgery compared with the standard 15 years ago when a 5 cm rule was used. Therefore, comparing series from this decade with series from the 1980s and 1990s will inevitably show more preserved sphincters now than then. Whether this change has anything to do with preoperative chemoradiotherapy is actually not known; rather the change in surgical attitude is more important than the effects of any preceding radio(chemo)therapy. As the Swedish Council of Technology Assessment in Health Care (SBU) pointed out [95], at this moment the literature is inconclusive in evaluating the role of preoperative radiotherapy alone or with V. Valentini et al. / Radiotherapy and Oncology 87 (2008) 449–474 concurrent chemotherapy in promoting sphincter-saving surgery in low-lying tumours. Sphincter preservation without good function is of questionable benefit. In fact, it is difficult to reliably measure actual sphincter function. Based upon reports, most patients are considered to have an acceptable to good function but as many as 20% will be more or less incontinent, not only for flatus or loose stool but also for solid stool [97]. It is apparently very difficult to interpret the literature on this topic, as cultural differences are enormous. It appears that a stoma is more or less disastrous for the patient and a failure for the surgeon in southern parts of Europe and the Arabic world. Therefore, many patients from the Mediterranean areas will accept poor bowel function in preference to a stoma, and also accept using diapers. In the northern parts of Europe, however, it is our clear impression that a stoma is more acceptable and data support that a stoma is frequently a better alternative in rectal cancer surgery than non-optimal bowel function. Based upon questionnaire studies stoma patients, as a group, do not have a worse quality of life than patients treated with sphincter preservation [98,99]. The surgical plane for Abdomino-Perineal Resection (APR) Pathological studies of the CRM at the level of the anorectal junction and anal canal sphincter show a high risk of tumor involvement. A waist is often created by the surgeon where the mesorectum terminates and the levator (m. puborectalis) inserts into the sphincter complex. The quality of surgery in the levator/anal canal area below the mesorectum varies between surgeons who may operate in different surgical planes. Quirke et al. have described these planes using specimens from the Dutch TME-Radiotherapy study in order to facilitate pathological grading of APR specimens analogous to mesorectal grading (see pathology section). This permits communication between the pathologist and surgeon in the MDT setting about the type and quality of surgery performed. These planes have been defined as: levator plane: the surgical plane lies external to the levators with them being removed en-bloc with the specimen. This creates a cylindrical specimen with the levators forming an extra protective layer on the sphincters. Sphincteric plane: either there are no levator muscles attached to the specimen or only a very small cuff and the resection margin is on the surface of the sphincters. The specimen has a waisted/apple core appearance. Intrasphincteric/submucosal plane: the surgeon has inadvertently entered the sphincters or even deeper into the submucosa or perforated the specimen at any point. Thus for an AR there will be a single mesorectal plane which has to be evaluated by the pathologist to certify the adequacy of the surgical procedure, but after an APR there will be two planes one for the mesorectum and one for the anal canal. It is crucial to have the correct strategy when an APR is performed. The dissection from above has to be stopped before entering the levator plane. The next step will be to dessect from below outside the sphincteric plane and by doing so finally divide the levators from below. By doing so a waist in the specimen, an ‘‘apple core’’ just at 457 the place of the tumour, can be avoided and prevent the specimen yielding a positive CRM [100,101]. Key points: Surgical • Loco-regional tumor control in rectal cancer surgery has changed dramatically during the past 10–15 years. The standard surgical technique is currently Total Mesorectal Excision (TME). In patients with a tumor in themiddle or distal third of the rectum, a TME is always indicated. • It has been claimed, mainly based upon historical controls, that radio-(chemo)therapy with delayed surgery will increase the number of preserved sphincters due to a downsizing effect on the tumor allowing more conservative surgeryin the lower third of the rectum. Unfortunately, there are no randomized trials supporting this idea. Furthermore,sphincter preservation without good function is of questionable benefit, although many patients from the Mediterranean areas will accept poor bowel function in preference to a stoma. • Pathological studies of the CRM at the level of the anorectal junction and anal canal sphincter show higher rates of CRM involvement due to dissection along the thinning mesorectum on to the anal sphincter. Radiotherapy and chemotherapy During the past decades a broad spectrum of treatment modalities have been examined such as postoperative chemoradiotherapy with different 5-fluorouracil (5-FU)-based schedules, preoperative radiotherapy short course (5 · 5 Gy in 5 days), long course (alone or in combination with 5-FU-based regimens or with new drugs), and intraoperative radiotherapy (IORT). These modalities are used differently in different parts of Europe and in North America, even if based upon the same evidence from studies performed in different parts of the world. We will analyze the evidence in the literature, focusing on the main advantages that any particular approach promotes for the different presentations of rectal cancer: early presentation, locally advanced, unresectable and recurrent; than we report some technical details for rectal tumour irradiation. Early rectal cancer Early localized tumors (3–5% of rectal cancers) include small, exophytic, mobile tumors without adverse pathologic factors (i.e. high grade, blood or lymphatic vessel invasion, colloid histology, or the penetration of tumor into or through the bowel wall) and can be adequately treated with a variety of local therapies such as local excision or endoluminal radiotherapy. Most investigators have used intraluminal irradiation alone or a combination of temporary Iridium-192 implant and external beam radiation for more advanced tumors (more than cT2 or N+) [102–106]. Intracavitary treatment was introduced by Papillion and colleagues in Lyon, France. They irradiated early tumors with a low-energy X-ray unit, placed through a 4-cm proctoscope almost against the tumor and generally doses of 30 Gy per treatment were given using this ‘‘contact’’ approach. Three or four such 458 Evidence and research in rectal cancer treatments were given over 1 month. Using this technique, local failure rates ranged between 10% and 15%. The overall 5-year survival ranges between 65% and 81%. For more advanced tumours local control rates are much lower [104,107–109]. Local excision has been performed both pre- and postradiation therapy. The main advantage of a local excision prior to irradiation is that pathologic details such as margins, depth of bowel wall penetration, and histological features are known. Patients with pT1 tumors without adverse pathologic factors have a low rate of local failure (5–10%) and positive nodes (<10%) and usually do not need adjuvant therapy. On the contrary, when adverse pathologic factors are present or the tumor invades into or through the muscularis propria, the local failure rate raises to at least 17% and the incidence of positive nodes to above 10% [110]. Many conservative surgical approaches are practiced; recently, Transanal Endoscopic Microsurgery (TEM) has emerged as a reliable option [111]. Regardless of the technique, excision should be full thickness, non-fragmented, and have negative margins [112]. If there is any doubt about this the patient must be offered either postoperative radio(chemo)therapy or an abdominal resection of the whole rectum. The high local failure rates for pT3 tumors suggest that they are treated more effectively with radical surgery and pre- or postoperative therapy. Salvage of local failures is possible after local excision and radiotherapy, and at least half of the patients who undergo a salvage abdomino-perineal resection (APR) can be cured [113–119]. A close follow-up is recommended. The few series that have investigated sphincter function report favourable outcomes [114–116,120–123]. Locally advanced rectal cancer The more locally advanced rectal cancers are tumours with penetration through the entire rectal wall or with evidence of involved pelvic nodes, but still a non-threatened CRM based upon preoperative MRI and without distant metastases. Preoperative radiotherapy The potential advantages of the preoperative approach include decreased tumor seeding, less acute toxicity, increased radiosensitivity due to more oxygenated cells, and according to some a potential for sphincter preservation [123]. The main disadvantage is related to overtreatment of patients with early stages (pT1-2N0) or undetected metastatic disease. This disadvantage has gradually become less important because imaging modalities (endorectal ultrasound and high-resolution phased array magnetic resonance imaging [MRI]) now allow better preoperative staging and prediction of a negative circumferential margin (CRM) [31,37,47]. There are more than 15 randomized trials of preoperative radiation therapy without concurrent chemotherapy for clinically resectable rectal cancer. All used low to moderate doses of radiation and most showed a decrease in local recurrence. The Swedish Rectal Cancer Trial is the only one out of eight studies with more than 500 patients, which reported a survival advantage for the total treatment group [124]. Three meta-analyses report conflicting results [125– 127]. All of them reveal a decrease in local recurrence. However, the analysis by Camma et al. [125] reported a survival advantage, whereas the analysis by Munro and Bentley [127] did not. The Swedish Council of Technology Assessment in Health Care (SBU) performed a systematic review of radiation therapy trials [95]. They analyzed data from 42 randomized trials and 3 meta-analyses, 36 prospective studies, 7 retrospective studies and 17 other articles, for a total of 25,351 patients. The main conclusion was that preoperative radiotherapy at biologically effective doses above 30 Gy decreases the relative risk of local failure by 50–70% and 30–40% for postoperative radiotherapy at doses that are usually higher than those used preoperatively (similar to the Colorectal Cancer Collaborative Group) [126] and that survival is improved by about 10% using preoperative radiotherapy. In the last years therefore preoperative therapy has gained wide acceptance as standard therapy for rectal cancer. Apart from the Upsala Study and the Swedish Rectal Cancer Trials, two prospective trials also have proven the efficacy of short-course preoperative radiotherapy [76,128]. Subgroup analysis, however, showed that this treatment does not seem effective enough for patients with a predicted positive CRM and low seated tumours [76]. A recent update of the Dutch Trial, which randomized one thousand eight hundred and 61 patients with resectable rectal cancer between TME preceded by 5 · 5 Gy or TME alone, with a median follow-up of surviving patients of 6.1 years, still showed a reduced five-year local recurrence risk for patients undergoing a macroscopically complete local resection: 5.6% following preoperative radiotherapy compared with 10.9% in patients undergoing TME alone (p < 0.001). Overall survival at 5 years was 64.2% and 63.5%, respectively (p = 0.902). Subgroup analyses reported a significant effect of radiotherapy in reducing local recurrence risk for patients with nodal involvement, for patients with lesions between 5 and 10 cm from the anal verge, and for patients with uninvolved circumferential resection margins [129]. The UK Medical Research Council Trial MRC CR07 randomized patients with clinical stages I–III rectal cancer to preoperative 5 · 5 Gy and TME or to selective postoperative radiochemotherapy, which was applied only for patients with a histologic CRM < 1 mm. Preliminary results showed local recurrence rates at 5 years of 5% and 11%, significantly favoring the unselected preoperative treatment approach [128]. The Norwegian Rectal Cancer Group recently reported a 20% local failure rate for 1676 patients with pT3 rectal cancer (11% for CRM > 3 mm, N0; 36,5% for CRM 6 1 mm, N2) treated without preoperative RT, indicating the need for neoadjuvant RT even after introduction of quality-controlled TME surgery [130]. It is not possible to accurately compare the local control and survival outcomes of short-course preoperative radiation with conventional preoperative combined modality therapy used more recently, because there is selection of more favourable patients in the series using short-course radiation. The conventional preoperative combined modality therapy regimens are now generally limited to patients with cT3-4 and/or N+ disease, whereas most trials that used 459 V. Valentini et al. / Radiotherapy and Oncology 87 (2008) 449–474 vorin, and all patients receive postoperative chemotherapy [133]. An improvement in the pCR rate was observed (12% vs 4%, p = 0.0001) and local recurrence was lower in preop RTCT: 8% vs 16.5% of preop RT (p = 0.004). Overall survival at 5 years was the same (67%), Grade 3+ toxicity was increased (15% vs 3%, p_0.0001) with preoperative RT-CT. There are insufficient data on adjuvant postoperative chemotherapy after preoperative treatment with (chemo)radiation to come to a conclusion about its use. In the EORTC 22921 trial postoperative chemotherapy had a non-significant influence on local relapse and relapse free and overall survival. Exploratory subgroup analyses suggest that only good-prognosis patients with downstaging of cT3-4 to ypT0-2 benefit from adjuvant CT [134]. This data supports that – as shown in other trials, e.g. the QUASAR trial with more than 800 patients or the Japanese trial investigating 5-FU/ FA or UFT, respectively, with a significant survival benefit of 3–4%. 5-FU based chemotherapy as part of the peri-operative treatment strategy has still to be investigated [135]. Since single agent 5-FU with or without leucovorin is a rather weak chemotherapy with a small but significant effect on colon cancer, the potential of adjuvant combination chemotherapy should be investigated. The 5-FU bolus or infused 5-FU as well as capecitabine has been combined in several phase II studies with oxaliplatin or irinotecan, in combination with radiation as well as adjuvant treatment after surgery. The toxicity of this combination is relatively low, at least in the preoperative setting combined with radiation. In the postoperative setting, the toxicity depends on the individual patient and the local situation after surgery and pre-op chemoradiation. In more recent studies, the tolerability of this adjuvant chemotherapy with drug combination, e.g. capecitabine and oxaliplatin, seems acceptable [136]. Although some series show no correlation [137,138], many series report that patients who achieve a pathological complete response (pCR) following preoperative radiotherapy ± concurrent chemotherapy have improved long-term outcomes in terms of excellent local control rates, indepen- short-course preoperative radiation included patients with cT1-3 disease. The main reason for this was that preoperative staging was not a routine procedure and generally less reliable at that time. However, a Polish trial randomized patients with resectable cT3-4 rectal cancer to 5 Gy · 5 followed by surgery (median 8 days) or conventional preoperative combined modality therapy (50.4 Gy plus bolus 5-FU/leucovorin daily · 5, weeks 1 and 5) followed by surgery (median 78 days) [131]. The tumors did not infiltrate the anorectal ring. Sphincter-saving surgery was the main end-point and was performed in 61% of patients treated with short-course and 58% with long course + concurrent chemotherapy (p = NS). Higher Grade 3 acute toxicity was observed in the radiochemotherapy arm. The actuarial 4year overall survival was 67% in the short-course group and 66% in the chemoradiation group (p = NS); no significant differences were found in disease-free survival, incidence of local recurrence and severe late toxicity: 58% vs 55%, 9% vs 14% and 10% vs 7%, respectively [131]. Two randomized trials have examined whether chemotherapy improves the results of preoperative radiation in patients with locally advanced rectal cancer (Table 1). The EORTC 22921 is a 4-arm randomized trial of preoperative 45 Gy with or without concurrent bolus 5-FU/leucovorin followed by surgery with or without four cycles of postoperative 5-FU/leucovorin. A significant decrease in local recurrence was observed in all 3 chemotherapy groups: 8.8%, 9.6% and 8.0% with either preop RT-CT, postop CT and both, vs 17.1% without (p = 0.002). Five years overall survival was not affected by chemotherapy at the median follow-up of 5.4 years: 66% vs 65% (p = 0.798) for preop RT-CT vs preop RT; 67% vs 63% (p = 0.132) for postop CT vs nil. An increased rate of pT0 (14% vs 5%, p = 0.0001) was observed, but no difference in sphincter saving surgery (52.8% vs 50.5%, p = 0.47); 42.9% of patients received planned adjuvant CT. The authors stated that in view of the benefit of preop RT-CT and the bad compliance of postop CT, preop RT-CT might be preferred [132]. The second trial (FFCD 9203) compared preoperative 45 Gy with or without bolus 5-FU/leuco- Table 1 Randomized trials of preoperative chemoradiotherapy vs preoperative radiotherapy in resectable rectal cancer Author Regimen Patients pCR (%) Spincter preservation (%) Local failure (%) 5 y DFS (%) 5 y OS (%) ]5 ] 50.5 ] 54 ] 65 ] 14 ] 52.8 17.1 9.6 8.7 7.6 p = 0.002 ] 56 ] 66 Preop Postop Bosset EORTC ‘06 [178] RT RT RT/5-FU RT/5-FU 5-FU/FA 1011 5-FU/FA p = 0.0001 Gerard FFCD ‘06 [179] Bujko Polish ‘07 [180] RT RT/5-FU RT (5 · 5 Gy) RT/5-FU 5-FU/FA 5-FU/FA 733 3.6 11.4 p = 0.0001 52 53 16.5 8.1 p = 0.003 56 59 66 67 312 0.7 15.2 p = 0.0001 61 58 9 14 58 55 67 66 5 y DFS: 5-year disease-free survival; 5 y OS: 5-year overall survival; , 4-year; RT: radiotherapy; 5-FU: 5-fluorouracil; FA: folinic acid. 460 Evidence and research in rectal cancer dent of their initial clinical T and N stage [81,98,139–142]. The different incidence of pCR in radiochemotherapy arms did not affect the final outcome of the randomized studies [131,132]. These data support the concept of heterogeneity between rectal cancers and the need to identify reliable markers to detect favourable patients who could be cured with less therapy. Analysis of pre-treatment biopsies using selected molecular markers such as VEGF [143], c-K-ras [144], thymidylate synthase [145], p27kip1 [146], p53 [147,148], apoptosis [149], DCC [147], and Ki-67 [150] have had varying success in identifying patients who may best respond to preoperative therapy. Since these studies are retrospective and usually do not examine multiple markers, at present the need for combined treatment should still be based solely on T and N stage. Postoperative radiotherapy The main advantage with this approach is better selection of patients based on pathologic staging. Postoperative therapy remains a common approach, particularly in North-America, despite advances in preoperative imaging techniques. The primary disadvantages include an increased toxicity related to the amount of small bowel in the radiation field [123], a potentially more radio-resistant hypoxic post-surgical bed and, if the patient has undergone an APR, the radiation field has to be extended to include the perineal scar. Five randomized trials have reported data on the use of adjuvant postoperative radiation therapy alone in stages pT3 and/or N1–2 rectal cancer [151–155]. None showed an improvement in overall survival. No survival advantage was observed from pelvic radiation plus elective para-aortic and liver radiation vs pelvic radiation alone [155]. In 1990, the NCI Consensus Conference, analyzing the postoperative North-American chemoradiotherapy studies, stated that combined modality therapy was the standard postoperative treatment for patients with pT3 and/or N1– 2 disease [156]. The standard design consisted of six cycles of chemotherapy with concurrent radiation during cycles 3 and 4. A 10% survival advantage from continuous infusion (CI) 5-FU vs bolus 5-FU combined with radiotherapy was reported in the Intergroup/NCCTG trial [157]. The INT-0144 postoperative adjuvant rectal trial also tested this question [158]: the patients were randomized to 3 arms: arm 1 = bolus 5-FU ! CI 5-FU/RT ! bolus 5-FU, arm 2 = CI 5-FU ! CI 5-FU/RT ! CI 5-FU and arm 3 = bolus 5-FU/LV/Levamisole ! bolus 5-FU/LV/Levamisole/RT ! bolus 5-FU/LV/ Levamisole. The lowest incidence of Grade 3+ haematological toxicity was seen in arm 2 (4%). However, there was no significant difference in local control or survival. Given these results, CI 5-FU with radiation is considered as standard and either arm 1 or 2 is a reasonable choice. A randomized trial by J.H.Lee et al. suggested that radiation should start during cycle 1 rather than during cycle 3 [159]. Even if this interesting result opens a new debate, a number of patients who did not receive the treatment arm were randomized, thus more data are needed before recommending a change in sequence. A small randomized Italian study showed no improved outcome for postoperative RT plus chemotherapy (5-FU plus levamisole) compared with postoperative RT alone, however, in this trial chemotherapy was applied before (1 cycle) and after RT (five cycles). Thus, this was a sequential rather than a concurrent RT-CT design [160]. Recently, the 6th edition of the American Joint Commission on Cancer (AJCC) staging system subdivided stage III into IIIA (T1–2N1), IIIB (T3–4N1), and IIIC (TanyN2), based on a pooled analysis of Intergroup and NSABP postoperative trials, and a retrospective analysis of the American College of Surgeons National Cancer Database (NCDB) [161]. In these analyses, the 5-year survival of no radiotherapy arms by stages IIIA, B and C was 81%, 57% and 49% in the pooled analysis and 55%, 35% and 25% in the NCDB database, respectively. Although radiation does not improve the survival achieved with chemotherapy alone in stages pT3N0, T1– 2N1 disease, local control data are requested before recommending chemotherapy alone for this subset of patients. If the local control rate without radiation is acceptable, then for pT3N0 upper rectal cancers patients, who undergo a total mesorectal excision and have at least 12 nodes examined, radiation therapy can be avoided. The 4–5% benefit in local control with radiation may not be worth the risks, especially not in women of reproductive age [123]. Acute toxicity is usually high with postoperative therapy: e.g. the incidence of Grade 3+ toxicity in the combined modality arms of the GITSG and Mayo/NCCTG 79-47-51 trials was 25–50%. Furthermore, the percentages of patients who completed the prescribed six cycles of chemotherapy in those trials were only 65% and 50%, respectively [162]. To reduce toxicity, the contribution of adjuvant chemotherapy in the postoperative combined treatment has been questioned. Two European randomized trials support the argument. The Norwegian trial compared surgery alone with surgery plus postoperative radiochemotherapy and a less resource-demanding 5-FU regimen (bolus injection) administered exclusively during the radiotherapy period. Five-year overall survival and disease-free survival rates were significantly better in the combined treatment arm (64% vs 50% and 64% vs 46%, respectively) [163]. Furthermore, the acute and long-term toxicity of the combined regimen was low. A Hellenic trial tested the addition of four cycles of chemotherapy with 5-FU and leucovorin to postoperative concomitant radiotherapy with 5-FU bolus infusion. No statistical difference in 3-year overall and disease-free survival was seen (70% vs 68% and 77% vs 73%, respectively). Concomitant radiotherapy and adjuvant four cycles of chemotherapy were more toxic than postoperative radiochemotherapy alone arm (32% vs 5%, p < 0.0001) [164]. Preoperative vs postoperative radiotherapy Preoperative and postoperative therapy have been compared in four randomized trials. The Uppsala trial used short-course radiation (5.1 Gy · 5) vs 60 Gy postoperatively with conventional fractionation [165]. The preoperative treatment arm resulted in a significant decrease in local failure (13% vs 22%) with no significant difference in survival (42% vs 38%). The other three randomized trials selected patients with T3–4 disease and used conventional radiation doses and concurrent 5-FU-based chemotherapy. Two are from the United States (INT 0147, NSABP R0-3) and one from V. Valentini et al. / Radiotherapy and Oncology 87 (2008) 449–474 Germany (CAO/ARO/AIO 94). Unfortunately, low accrual resulted in early closure of both the NSABP R-03 and INT 0147 trials. The German trial completed the planned accrual of over 800 patients and compared preoperative combined modality therapy (with CI 5-FU) vs. postoperative combined modality therapy [85]. Patients were stratified by the surgeon, in order to overcome surgical bias. The preoperative group had a significant decrease in local failure (6% vs 13%, p = 0.006), acute toxicity (27% vs 40%, p = 0.001), late toxicity (14% vs 24%, p = 0.012) compared with the postoperative group. In a subgroup of 194 patients judged by the surgeon to require an APR and randomized to receive preoperative combined modality therapy, a significant increase in sphincter preservation (39% vs 20%, p = 0.004) was observed. However, it is not known how this group was selected, and more importantly no data are available whether this change in surgical strategy has increased the local failure rate. With a median follow-up of 40 months there was no difference in 5-year survival (74% vs 76%). At the present time, given the improved local control, acute and long-term toxicity profile, and sphincter preservation rate reported in the German trial, patients with cT3 rectal cancer who require combined modality therapy should receive it preoperatively. Unresectable rectal cancer Adenocarcinomas of the rectum beyond potentially curative surgical resection (R0) are defined as unresectable. The evaluation of resectability depends on the extent of the operation the surgeon is able to perform as well as on the morbidity the patient is willing to accept. Unresectable rectal cancer is a heterogeneous disease and it is not unequivocally related to cT4 stage: it can range from a tethered or ‘marginally resectable’ cancer to a fixed cancer with direct invasion of adjacent non-resectable organs or structures. The heterogeneity of presentation and the absence of a uniform definition of resectability may explain some of the variations in outcomes seen among series [95]. All patients with primarily unresectable disease should receive preoperative combined modality therapy in the range of 50–54 Gy plus 5-FU-based chemotherapy to enhance R0 resectability [95]. More recently, the preliminary outcome of a randomized Scandinavian Trial on preoperative radiochemotherapy vs only radiotherapy in unresectable and recurrent patients showed a statistical advantage for combined therapy in disease-free survival (64% vs 50% at 5 years, p = 0.012) and overall survival (72% vs 53% at 5 years, p = 0.025), and seems to further support the role of preoperative radiochemotherapy [166]. Attempts to increase the dose using concomitant or sequential boosts have also been practiced [167–169]. Although 50–90% will be able to undergo a resection with negative margins, depending on the degree of tumour fixation, many still develop a local recurrence. Given the limitation of the total radiotherapy dose which can be delivered to the bulky tumor in the pelvis [170] and the frequent problem of local recurrence, the surgeon should be aggressive and not risk leaving microscopic residual tumour [171]. Extended surgery is still recommended even if there is a favourable response after preoperative therapy. 461 To increase local control a large single dose of radiation can be delivered to a surgically exposed area, while uninvolved and dose-limiting tissues are displaced [172]. Intraoperative radiation therapy (IORT) can be delivered by two techniques: electron beam and brachytherapy. Brachytherapy is commonly delivered by the high-dose rate (HDR) technique and the dose rate is similar to that used for electron beam IORT [173–176]. The results (and recommended dose) of IORT depend on whether the margins of resection are negative or whether there is microscopic or gross residual disease. In general, series have used 10–20 Gy. North American and European experiences from single institution studies suggest a favourable effect in patients who also have positive margins and microscopic residual disease [177–181]. IORT-related toxicity increases with IORT doses >20 Gy. Recurrent tumor Usually, patients with local recurrence have a very unfavourable prognosis. Symptoms include pain, hemorrhage, pelvic infection and obstructive symptoms. The median survival ranges between 1 and 2 years [182]. The incidence of failure sites were analyzed in 155 patients at the University of Wurzburg [183]. They are similar for APR vs low anterior resection (LAR): local + nodal: 61% vs 66%, isolated lymph node: 4% vs 5%, internal iliac and presacral nodes: 47% vs 59% and external iliac: 7% vs 2%. Local recurrence was most commonly seen in the presacral pelvis and in patients who underwent a LAR the anastomosis was involved in 93%. Attempts to classify local pelvic recurrence according to tumor location within the pelvis have been described. At the Mayo Clinic, 106 patients with local recurrence treated by IORT and postoperative radiotherapy were stratified during the surgical procedure according to the infiltration of tumor as none (F0), one (F1), two (F2), or >2 pelvic sites (F3) [184]. This classification system significantly correlated with survival. As with primarily unresectable disease, patients should receive preoperative combined modality therapy, but the role of higher doses is less clear, probably due to the heterogeneity of the patient population. Negative margins seem to predict better outcome. IORT offers conflicting results: in the MGH series of 40 patients, the 5-year local control and 5-year survival were higher with negative margins (56% and 40%) vs positive margins (13% and 12%) [185]. Similar results were reported in 74 patients treated at Memorial Sloan Kettering [174]. In a report from Olso, 107 patients with isolated pelvic recurrence received 46–50 Gy preoperatively [186]. Regardless of the volume of residual disease, there was no significant difference in local recurrence or survival whether or not they received IORT. Although the combination of adjuvant therapy and TME has significantly lowered the incidence of local recurrence, there is a subset of patients previously irradiated who present with only local recurrence. In these patients, re-irradiation would be expected to be associated with a high risk of late toxicity. Few studies have analyzed the role of radiation retreatment in pelvic recurrence. Data from Mohiuddin and colleagues suggests re-irradiation with doses of 30 Gy, and if the small bowel can be excluded from the irradiation field, 40 Gy can be used for limited volumes [187]. A 462 Evidence and research in rectal cancer multi-center Italian trial of 59 patients with recurrent disease who had received <55 Gy were retreated preoperatively with concurrent 5-FU plus 30 Gy (1.2 Gy BID) to the GTV plus a 4-cm margin [188]. A boost was delivered, with the same fractionation schedule to the GTV plus a 2-cm margin (10.8 Gy). Grade 3+ acute and late toxicities were 5% and 12%, respectively. With a median follow-up of 36 months, local failure was 48%, median survival 42 months, and 5-year actuarial survival 39% (R0: 67% vs. R1–2: 22%). Techniques of irradiation Patterns of relapse that define radiation portals The design of pelvic radiation therapy fields is mainly based on the knowledge of local-regional failures after surgery. These occur as a result of both residual disease in the soft-tissues of the pelvis as well as from residual nodal disease. For locally advanced disease, recurrences in the soft tissues may arise from tumor extension to the pelvic sidewall, the bladder, prostate in men, the vagina in women, and the presacral space in all patients. This is especially true for tumors penetrating the mesorectal fascia or those with involved or close (<1 mm) circumferential margins. Incomplete mesorectal excision is also at higher risk to leave residual microscopic tumor cells behind. The major lymphatic spread is in a cephalad direction contained within the perirectal fascia and along the mesorectum/mesocolon, that is commonly dissected by standard TME surgery. Outside the mesorectum is a space containing vessels, nerves and lymphatics, that is not usually dissected. Surgical series reported by Japanese surgeons who excised rectal cancers with radical lymph node dissection extending to the lateral space have shown that lesions at or below the peritoneal reflexion tend to spread laterally along the internal iliac and obdurator chains [189]. The external iliac nodes may only become at risk with anterior tumor extension and adjacent organ involvement. Lesions that extend to the anal canal or the lower third of the vagina can spread to the inguinal nodes. The relative frequency and sites of pelvic failures were delineated by the early work of Gunderson and Sosin [190]. In this re-operative series of 75 patients (91% were initially treated with an APR), failure sites included soft-tissue of the pelvis or the anastomotic site: 69%, pelvic lymph nodes: 42% and the perineum: 25%. A more contemporary series of 269 patients by Hruby et al. confirmed that the majority of local failures occurred in the posterior central pelvis (47%) or at the anastomosis (21%), while anterior recurrences (11%) were mainly seen in T4 tumors. Perineal recurrences occurred in 16% of patients who underwent APR [191]. Irradiation fields The whole pelvic radiation field should adequately cover the primary tumor/tumor bed as well as the primary nodes at risk. The intent of the boost is to treat the primary tumor and not to include clinically uninvolved nodes. Therefore, the exact size is determined by the size and location of the primary tumor. Whole pelvic and boost fields are usually treated with three-field (PA and lateral) or four-field (lateral and paired posterior obliques) techniques. A three-field techniques allows more sparing of anterior pelvic structures. Field shaping by blocks is used to spare additional small intestine anteriorly and superiorly, the posterior muscle and soft tissue behind the sacrum, and inferior to the symphysis pubis [123]. Three dimensional (3D) conformal treatment planning and IMRT Innovative techniques using 3D conformal treatment planning are being investigated. The most important contribution of 3D treatment planning was the ability to plan and localize the target and normal tissues at all levels of the treatment volume, and to obtain dose volume histogram data. Based on the predominant locations of local recurrences described above and the frequency of lymph node involvement, Roels et al. proposed guidelines for the definition and delineation of the clinical target volume (CTV) in rectal cancer [192]. They proposed to include the primary tumor, the mesorectal and posterior sub-site as well as the lateral lymph nodes in the CTV for all patients. Moreover, they suggested inclusion of the inferior pelvic sub-site i.e. the anal triangle of the perineum, containing the anal sphincter complex with the surrounding perianal and ischiorectal space, in the CTV if the tumor is located within 6 cm from the anal margin and the surgeon aims at a sphinctersaving procedure, or the tumor invades the anal sphincter and an APR is necessary. A randomized trial of conformal vs conventional radiation therapy in 266 evaluable patients with pelvic malignancies has been reported by D.M. Tait Patients were treated with a three-field technique with 6 Mv photons and the most common dose was 64 Gy in 2 Gy fractions [193]. Although there was a decrease in the volume of normal tissue volumes in the radiation field with conformal vs conventional treatment (689 cm3 vs. 792 cm3) there was no difference in the level of symptoms or in medication prescribed. R.J. Meyerson useda 3D planned boost radiotherapy (0.9 Gy once or twice weekly to a total boost dose of 4.5–9 Gy) concurrently with pelvic irradiation (45 Gy/25 fractions) [167]. Dose volume histogram information correlated with Grades 3–4 toxicity, particularly with respect to small bowel complications. The authors concluded that every effort should be made to limit the volume of small bowel receiving more then 40 Gy to less than 120 cc. Using a 3D planning system, Koelbl et al. found that in patients receiving postoperative radiation, the use of the prone position plus a belly board decreased the small bowel volume treated vs the supine position [194]. 3D planned radiotherapy is desirable for patients who undergo re-irradiation in order to limit dose to previously irradiated critical structures. The use of intensity-modulated radiotherapy (IMRT) may further lower the dose to critical structures while maintaining adequate doses in the planning target volume, but caution is required because this technique is still under clinical evaluation [195,196]. Irradiation dose A meta-analysis of patients who received preoperative radiation with a variety of doses and fraction sizes concluded that biologically effective doses above 30 Gy, compared with less than 30 Gy, resulted in a statistically V. Valentini et al. / Radiotherapy and Oncology 87 (2008) 449–474 significant reduction in local-regional recurrences [126]. With conventional fractionation (1.8–2 Gy fractions, 5 days per week), the doses most commonly used for the whole pelvis fields for either pre- or postoperative irradiation are in the range of 45–50.4 Gy in 5–6 weeks. These doses are necessary to control microscopic disease [197]. A boost of 5.4 y to the primary tumor or tumor bed may be delivered if the small bowel is excluded from the high dose field. However, it is not clear that higher doses improve local control. Higher preoperative doses to 60 Gy are associated with increased pCR rates, however, they may also significantly increase acute and long-term morbidity. The RTOG R-0012 phase II randomized trial compared BID preoperative chemoradiation up to 60 Gy (1.2–45.6 Gy, with a boost of 9.6-14.4 Gy) with conventional fractionation (1.8–45 Gy, with a boost of 5.4–9.0 Gy) plus 5-FU/irinotecan [198]. Both regimens resulted in a 28% pCR rate, but were also associated with a >40% rate of Grades 3–4 acute toxicity. In the postoperative setting, if there is incomplete resection (R1 or R2 resection), radiation doses of >60 Gy are required. External beam radiotherapy is limited in this situation by normal tissue tolerance, and results for patients with residual disease who received postoperative external radiation therapy are disappointing [199,200]. As previously discussed, IORT may help to overcome this problem by direct visualization and irradiation of the persistent tumor. Complications of pelvic radiation therapy are a function of the volume of the radiation field, overall treatment time, fraction size, radiation energy, total dose, technique and sequence of radiotherapy [201]. Small bowel related complications are directly proportional to the volume of small bowel in the radiation field [202]. In patients receiving combined radiation and chemotherapy, the volume of small bowel in the radiation field limits the ability to escalate the dose of 5-FU [201]. Key points: Radiotherapy and Chemotherapy • Early localized tumors can be adequately treated with a variety of local therapies such as local excision or endoluminal radiotherapy. If a patient is offered a local surgical strategy, it is important to validate the quality of the specimen as well as adverse pathological factors. • More than 15 randomized trials and three meta-analyses revealed a decrease in local recurrence, whereas conflicting results for survival advantage are still reported. A systematic review of radiation therapy trials indicates that survival is improved by about 10% using preoperative radiotherapy. Preoperative therapy has gained wide acceptance as standard therapy for rectal cancer. • It is not possible to accurately compare the local control and survival outcomes of short-course preoperative radiation with conventional preoperative combined modality therapy used more recently, because there is more favourable patient selection in the series using short-course radiation. Subgroup analysis, however, shows that short-course radiation does not seem effective enough for patients with a predicted positive CRM and possibly low seated tumours. 463 • Two randomized trials (EORTC 22921 and FFCD 9203) have examined whether chemotherapy improves the results of preoperative radiation in patients with cT3-4 rectal cancer. Both studies showed in chemotherapy groups:decrease in local recurrence, an increased rate of pT0 and Grade 3+ toxicity, no benefit of overall survival at 5 years. • A Polish trial randomized resectable cT3-4 patients to 5 Gy · 5 followed by surgery or preoperative chemoradiotherapy. No differences in sphincter preservation, local control, 5-year survival and late toxicity were observed. • The main advantage of postoperative radiotherapy is better selection of patients based on pathologic staging. No randomized trial of adjuvant postoperative radiation therapy alone has shown an improvement in overall survival. In 1990, the NCI Consensus Conference, analyzing the postoperative North American chemoradiotherapy studies, stated that combined modality therapy was the standard postoperative treatment for patients with pT3 and/or N1–2 disease. Acute toxicity is usually high with postoperative therapy. • Preoperative and postoperative therapy have been compared in four randomized trials. In the Germany trial (CAO/ARO/AIO 94) the preoperative group had a significant decrease in local failure, acute toxicity, late toxicity, significant increase in sphincter preservation and no difference in 5-year survival. At the present time, patients with cT3-4 rectal cancer who require combined modality therapy should receive it preoperatively. • There are no firm data with level 1 evidence on the role of adjuvant postoperative chemotherapy after preoperative treatment with (chemo)radiation, but the accumulation of data from several randomized trials seems to underline an effect of adjuvant chemotherapy. • Unresectable rectal cancer is a heterogeneous disease: it depends on the extent of the operation the surgeon is able to perform as well as the morbidity the patient is willing to accept. All patients with primarily unresectable disease should receive preoperative combined modality therapy in the range of 50–54 Gy plus 5-FU-based chemotherapy to enhance R0 resectability. Experience of increasing the dose using concomitant or sequential boosts has been reported. Extended surgery is still recommended even if there is a favourable response after preoperative therapy. • To increase local control a large single dose of radiation is delivered to a surgically exposed area (IORT), while uninvolved and dose-limiting tissues are displaced. North American and European single institution studies support a favourable effect in unresectable patients. • Patients with local recurrence have a very unfavourable prognosis: the median survival ranges between 1 and 2 years. Attempts to classify localized pelvic recurrences according to the tumor location within the pelvis have been practiced. Patients should receive preoperative combined modality therapy, IORT offers conflicting results. Re-irradiation is under clinical evaluation in recurrent patients previously irradiated. 464 Evidence and research in rectal cancer Treatment toxicity and quality of life The use of radiotherapy definitely diminishes the risk of local recurrence [95] and has been claimed by some to increase the number of preserved sphincters. However, there is strong evidence from the literature that bowel function will be adversely affected by both preoperative [99,203,204] and postoperative irradiation [205]. In very low anastomoses, some surgical procedures can ameliorate the quality of sphincter function and some types of colonic reservoir construction will improve bowel function [206–209]. In cases where the whole sphincter area has to be excised the destroyed sphincters can be restored by the use of a stimulated graciloplasty. The sigmoid colon is placed as a perineal stoma and the gracilis muscle is wrapped around the bowel as a neo-sphincter, which can be stimulated with a pacemaker, and, in such a way, act as a continent sphincter. In essence, the patients will be left with a perineal stoma and sphincter function will be supported by this stimulated graciloplasty. While preliminary reports were very optimistic, after a longer follow-up it is obvious that these patients do not have a normal life. They need enemas to evacuate the bowel and all of them need a pad due to soiling [210–213]. A common technique used today to make stoma care more convenient for the patient is to use a retrograde irrigation system, where patients are empty the bowel every second or third day using an enema. By doing so only a pad is needed to cover the stoma instead of stoma bag [214]. During combined modality treatments, acute side effects such as diarrhea and increased bowel frequency (small bowel), acute proctitis (large bowel), and dysuria are common [215]. These conditions are usually transient and resolve within a few weeks following the completion of radiation. The symptoms appear to be a function of the dose volume and fraction size rather than the total dose. The bowel mucosa usually recovers completely in one to three months following radiation. Management involves the use of antispasmodic and/or anticholinergic medications. The use of concurrent chemotherapy, especially 5-FU which has significant GI toxicity, will exacerbate the acute GI effects. The most common delayed severe complications are due to small bowel damage and include small bowel enteritis, adhesions and small bowel obstruction requiring surgical intervention. The incidence of small bowel obstruction requiring surgery following postoperative pelvic radiation for rectal cancer is 4–12% in historical series. In the MGH series, the incidence of small bowel obstruction with postoperative radiation therapy was 6% as compared with 5% with surgery alone [216]. It was 2% in the preoperative arm of the German CAO/ARO/AIO-94 trial [85]. Some evidence from long-term analysis of the Upsala and Swedish Trials supports an increased risk of second cancers in patients treated with RT in addition to surgery for a rectal cancer. This was mainly explained by an increase in the risk of second cancers in organs within or adjacent to the irradiated volume. However, a favorable effect of radiation seemed to dominate, as shown by the reduced risk of the sum of local recurrences and second cancers [217]. In addition to worsened bowel function, urogenital dysfunction after rectal cancer treatment is often reported [218–223]. Both radiotherapy and surgery contribute to the development of urogenital dysfunction [221,223–226]. The cause of radiotherapy-related urogenital dysfunction is multifactorial, involving fibrosis, vascular toxicity, neurotoxicity and psychological factors [227]. Depending on the dose and irradiation field, radiotherapy may cause fibrosis of the bladder and urethral sphincters, resulting in urinary dysfunction [227]. Radiotherapy has been shown to lead to increased sexual dysfunction, with a long-term deterioration of ejaculatory and erectile function due to late radiation damage to the seminal vesicles and small vessels, respectively [204]. Furthermore, surgical damage to pelvic autonomic nerves might be involved. During presacral mesorectal dissection damage to the superior hypogastric plexus and hypogastric nerves can occur, resulting in urinary incontinence, ejaculatory dysfunction in male patients and reduced lubrication in female patients [228]. During dissection of the lateral planes of the mesorectum deep in the pelvis the sacral splanchnic nerves and the inferior hypogastric plexus are at risk, leading to urinary retention, erectile disorders in male patients and reduced labial and vaginal swelling in female patients [225,228,229]. Patients treated with APR have more difficulties in voiding, erectile dysfunction and dyspareunia, compared with LAR patients [218,228,230,231]. This can be explained by the fact that more nerve damage occurs in APR patients, especially during the perineal phase, during which the distal branches of the pelvic autonomic nerves are at risk [228]. Because exact nerve identification can be difficult, the use of a nerve stimulating device could possibly facilitate preservation of the pelvic autonomic nerves during TME [232]. Key points: Treatment toxicity and quality of life • Acute side effects such as diarrhea and increased bowel frequency (small bowel), acute proctitis (large bowel), and dysuria are common during treatment. The symptoms appear to be a function of the dose volume and fraction size rather than the total dose. Delayed complications occur less frequently but are more serious. The initial symptoms commonly occur 6–18 months following completion of radiation. • There is strong evidence from the literature that bowel function will be further impaired after both preoperative and postoperative irradiation. Some surgical techniques could help preserve bowel function: colonic reservoir construction, stimulated graciloplasty, retrograde irrigation system. Urogenital dysfunction after rectal cancer treatment is often reported, both radiotherapy and surgery contribute to its development. Follow-up The main aim of clinical follow-up is to improve survival. This is achieved in two ways, by detecting recurrence of primary disease or development of a metachronous tumor. Other goals of the follow-up are: management of the posttreatment late complications, improvement of the patient– doctor relationship and quality control of the combined therapy outcome. The value of following patients after radical resection for colorectal cancer is still controversial, mainly since scientific evidence supporting it remains sparse. Many cohort V. Valentini et al. / Radiotherapy and Oncology 87 (2008) 449–474 and case-control studies have supported the effectiveness of follow-up [233] but, very few randomised controlled trials have been performed regarding follow-up and cancer mortality [234]. Moreover, the frequency of follow-up is still debatable. Outcome of follow-up programmes can be considered from both efficacy and cost perspectives [235]. Nevertheless despite limited evidence, follow-up programmes are being used in most clinics treating colorectal cancer patients [236]. Two systematic reviews with meta-analyses were published the same year investigating the same five randomised controlled trials [237,238], with the same conclusion: more intensive follow-up decreases mortality in colorectal cancer compared with sporadic or less intensive follow-up. Subsequently, another randomised study not included in the meta-analyses was published and confirmed this conclusion [239]. An important observation from all trials included in the meta-analyses is the heterogeneity seen in both intense and less intense follow-up regimens. Moreover, individual trials used different control modalities and, in fact, the intensity of control in one study could be considered more aggressive than the ‘‘intensive’’ group in other studies. The quality of surgery in these trials has also been questioned, as very high local recurrence rates were seen in the two studies which showed most benefit from intensive follow-up [240]. The results of these meta-analyses should, thus, be viewed with caution. One can argue – as some authors claim – that we know enough to make evidence-based recommendations [241]. The most crucial criticism of meta-analyses is that they are not able to identify either which follow-up modality to use, or the intensity (i.e. investigation intervals) of the follow-up. Nevertheless the published studies do imply that finding extraluminal recurrences (local recurrence after rectal cancer and liver metastases after colorectal cancer) is the main benefit in the follow-up program. Since local recurrence after colorectal cancer surgery is much less common than previously,the principal benefit remains in finding liver and possibly lung metastases, giving the opportunity for a second curative procedure. A subgroup analysis of three studies looking for liver metastases shows an effect on survival in one of the meta-analyses [237]. However, this could be an effect of less active preoperative staging of the liver and lung, which is more routine now but was not so when these referred trials were conducted. The search for intraluminal recurrence does not alter mortality, however, the detection of metachronous malignancy may be worthwhile. R.L.Cali reported the calculated annual incidence of 0.35% for metachronous lesions, with cumulative incidence at 18 years of 6.3% [242]. Of course, these figures would be much higher if we were to add the number of premalignant lesions discovered. In conclusion, the effect of high-volume follow-up programmes after radical surgery for colorectal cancer on overall survival is still not sufficiently elucidated to propose evidence-based guidelines. Despite this the Current Oncological Practice (COP) is moving towards high intensity follow-up programmes [243–245]. A minimum acceptable practice (MAP) might be just as good and based on the diagnostic tools available country by country. Based upon these 465 arguments a randomized trial has started in the Scandinavian countries to evaluate the frequency of follow-up. Patients are randomised to high- or low-volume control programmes. The same package of investigation is performed at each scheduled visit; serum CEA, CT abdomen + CT Thorax or thorax X-ray. The low-volume group is investigated after 12 months and 36 months, and the high-volume group every 6 months up to 36 months. The patients in both groups are followed until 5 years after radical surgery. The end-point is overall survival (http://www.colofol.cum). Key points: Follow-up • The main aim of follow-up is to improve survival. Published studies imply that finding extraluminal recurrences (local recurrence after rectal cancer and liver metastases after colorectal cancer) is the main benefit from the follow-up program. The exact value of following patients after radical resection for colorectal cancer is still controversial, however. Moreover, the frequency of follow-up is still debatable. Nonetheless, despite sparse evidence, follow-up programmes are being used in most clinics treating colorectal cancer patients. • Two systematic reviews with meta-analyses were published with the same conclusion: more intensive follow-up decreases mortality in colorectal cancer compared with sporadic or less intensive follow-up. The results of these meta-analyses have been criticised over the quality of surgery, preoperative staging and the intensity of follow-up in the controls, and they should be viewed with caution. Scenario of ongoing research Organ preservation represents one of the ongoing topics of surgical research: the experience with preoperative radiation + 5-FU based concomitant chemotherapy followed by local excision is at its beginning [100,113–115,246]. Most series are limited to highly selected patients with cT3 disease who are either medically inoperable or refuse radical surgery. Since most series limit this approach to those patients who responded to preoperative therapy there is a need to identify prognostic and predictive factors to better define patients who are suitable for limited surgery. Ongoing trials are accruing patients. It can even be questioned if a local excision can be avoided if the tumour has regressed completely following radiotherapy. Intensive follow-up with the ‘‘wait-and watch’’ philosophy has been used with impressive results, similar to those seen after radiotherapy for anal carcinoma [247]. This treatment policy has been adopted in patients where an abdomino-perineal resection has been the alternative procedure. There are studies underway which compare short-course vs long-course preoperative radiotherapy. Hopefully these studies will create an opportunity for a more tailormade approach based on stage, location of the tumour and the prediction of the CRM [248]. Data from the Uppsala group have showed that short-course radiotherapy and delayed surgery in T4 tumours based upon MRI-staging will also have R0 resection, indicating that down-sizing will occur after this treatment regimen [249]. 466 Evidence and research in rectal cancer The open questions of intensification of preoperative chemoradiation and postoperative adjuvant treatment are currently addressed by three current large trials (CAO/ARO/ AIO-04 in Germany, PETACC 6 in Europe and NSABP R-04 in the US). They investigate the value of oxaliplatin in addition to preoperative chemoradiation with 5-FU (CAO/ARO/AIO04) or capecitabine (PETACC 6) as well as in the postoperative phase for the prolonged period of 4–5 months. The primary end-point of these trials is disease-free survival at three years after preoperative infusional 5-FU (CAO/ARO/AIO-04) or capecitabine (PETACC-6) combined with oxaliplatin modulated chemoradiation, followed by TME and another 12 or 18 weeks of adjuvant 5-FU/oxaliplatin or capecitabine/oxaliplatin, respectively. The control arm of both trials is 5-FU or capecitabine modulated radiation, followed by TME and adjuvant systemic therapy with 5-FU or capecitabine, respectively. Secondary end-points are pathological response rates, sphincter preservation, local failure rate and toxicity. In addition the NSABP R-04 trial compares capecitabine with 5-FU in a 2 · 2 factorial design with or without oxaliplatin. In the PETACC study 5-FU has been substituted by capecitabine, since phase II studies showed good tolerability, easy administration and comparable, promising results, if combined with preoperative radiation with or without oxaliplatin. For postoperative single agent 5-FU, capecitabine is not investigated, however, the necessary information regarding the use of capecitabine instead of infusion or bolus 5-FU (±Folinic acid) can be derived from stage III colon cancer (IMPACT Trial). In patients treated with 5 · 5 Gy preoperative radiation, postoperative chemotherapy has not been evaluated so far but is currently being tested in a randomised trial (SCRIPT trial, ‘‘simply capecitabine in rectal cancer after irradiation plus TME’’). An Italian trial (INTERACT-LEADER) is testing a combination of preoperative radiotherapy with capacitabine and oxaliplatin against accelerated radiotherapy by concomitant boost and only capecitabine; the cT3N0-1 MRI responder patients receive local excision, and if pCR is confirmed no further surgery will follow. The next generation of clinical trials is about to start now and will integrate the novel ‘targeted’ drugs like bevacizumab and cetuximab in both preoperative and postoperative setting. The Epidermal growth factor receptor (EGFR) is a promising target of antitumor treatment because it participates in cell division, inhibition of apoptosis, and angiogenesis. Preclinical investigations have linked EGFR expression with radioresistance [250]. Clinical studies have established EGFR expression as an independent predictor of poor tumor response and prognosis in rectal cancer patients treated with preoperative CRT [251,252]. Hofheinz et al. performed a phase I trial of preoperative RT with capecitebine, irinotecan and cetuximab; and demonstrated that such a combination can be safely applied without dose compromises of the respective treatment components [253]. Machiels et al. have reported the safety and efficacy of combining preoperative RT with capecitabine and cetuximab in a phase I/II trial [254]. This combination was associated with no unexpected toxicity, and full doses of RT, CT, and cetuximab could be applied. However, only 5% of patients achieved a pCR, and a total of 68% had only moderate or minimal tumor regression. Rodel et al. conducted a multicenter phase I/II study to determine the tolerability and efficacy of adding cetuximab to preoperative RT with capecitabine and oxaliplatin [255]. Again, only 4 of the 45 operated patients (9%) had pCR in the resected specimen, and 53% of patients had only moderate or minimal tumor regression. The results of these clinical trials are intriguing and should stimulate more intense preclinical investigations in order to establish the best sequence of triple combinations. Inhibition of vascular endothelial growth factor (VEGF) via an anti-VEGF antibody (bevacizumab) has been shown to block the growth of a number of human cancer cell lines, including colorectal, in nude mice. Recent experimental studies in human tumor xenograft models indicate that VEGF blockade serves as a potent enhancer of RT [143]. The Duke University Medical Center Group has reported on two phase I studies of preoperative RT with bevacizumab and 5-FU, or oxaliplatin/capecitabine, respectively [143,252]. Preliminary data indicate safety of this regimens and significant activity. In a meticulous analysis of the first 6 patients performed 12 days after the first bevacizumab infusion, this group revealed a significant decrease in tumor blood perfusion and blood volume, and a significant decrease in tumor microvessel density. This was accompanied by a decrease of the interstitial fluid pressure, indicating that a ‘‘normalization’’ of the tumor vasculature by anti-VEGF treatment may contribute to the high efficacy of bevacizumab in this trial. Furthermore, the early onset of highly active systemic combination treatment before chemoradiation and TME is currently being investigated in phase II trials. Both approaches indicate that advanced rectal cancer has become a real ‘multimodal entity’, requiring improvement in all the fields of surgery, radiation and chemotherapy for optimal local control and reduction of distant metastases in order to improve overall prognosis. It is also clear, that in the face of current and future schedules and the increasing number of therapeutic options and intensities, translational research is urgently required for the identification of patient groups, by both clinical– pathological features and molecular and genetic markers, that will gain maximum benefit from each treatment option. In this time of changing therapeutic approaches, it clearly appears that a common standard for large heterogeneous patient groups will prospectively be substituted by more individualised therapies in the future. Key points: Scenario for ongoing research • Organ preservation represents one of the current topics for surgical research. Favourable long-term local control, metastasis-free survival and overall survival in patients with pCR support the concept of heterogeneity between rectal cancers and the need to identify patients who could be cured with less therapy. Local excision or intensive follow-up with the ‘‘wait-and watch’’ philosophy has been used. Ongoing trials are accruing patients. • Intensification of preoperative chemoradiation and postoperative adjuvant treatment are currently addressed by the use of drugs like oxaliplatin and capecitabine used effectively in colon cancer.Short-course radiotherapy and delayed surgery is also under clinical evaluation. V. Valentini et al. / Radiotherapy and Oncology 87 (2008) 449–474 • The Epidermal growth factor receptor (EGFR) and Vascular endothelial growth factor (VEGF) are promising targets of antitumor treatment. Results of clinical trials are intriguing and should stimulate more intense preclinical investigations. • In this time of changing therapeutic standards, it clearly appears that a common standard for large heterogeneous patient groups will be substituted in the future by more individualised therapies based on clinical– pathological features and molecular and genetic markers. Acknowledgements We express our gratitude to many colleagues and collaborators with whom we work together in the design and accomplishment of ESTRO Teaching Course on ‘ Evidences and Research in Rectal Cancer’, and in the revision of this manuscript, especially B. Barbaro, G.L. Beets, C. Coco, A. Crucitti, I. Dimitrijević, M.A. Gambacorta, S. Pucciarelli. C. Ratto, F.M. Vecchio. * Corresponding author. Vincenzo Valentini, Department of Radiation Oncology, Università Cattolica S.Cuore, Largo A.Gemelli,8, 00168 Rome, Italy. E-mail address: vvalentini@rm.unicatt.it Received 22 January 2008; received in revised form 14 May 2008; accepted 15 May 2008 References [1] Glimelius B. Introduction to optimal management of rectal cancer. EJC Supplements 2005;65:345–7. [2] Ferlay J, Autier P, Boniol M, et al. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 2007;18:581–92. [3] Cress RD, Morris C, Ellison G, et al. 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